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1.
Pharmacogenet Genomics ; 34(4): 105-116, 2024 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-38470454

RESUMEN

OBJECTIVES: Genetic variation has been a major contributor to interindividual variability of warfarin dosage requirement. The specific genetic factors contributing to warfarin bleeding complications are largely unknown, particularly in Chinese patients. In this study, 896 Chinese patients were enrolled to explore the effect of CYP2C9 and VKORC1 genetic variations on both the efficacy and safety of warfarin therapy. METHODS AND RESULTS: Univariate analyses unveiled significant associations between two specific single nucleotide polymorphisms rs1057910 in CYP2C9 and rs9923231 in VKORC1 and stable warfarin dosage ( P  < 0.001). Further, employing multivariate logistic regression analysis adjusted for age, sex and height, the investigation revealed that patients harboring at least one variant allele in CYP2C9 exhibited a heightened risk of bleeding events compared to those with the wild-type genotype (odds ratio = 2.16, P  = 0.04). Moreover, a meta-analysis conducted to consolidate findings confirmed the associations of both CYP2C9 (rs1057910) and VKORC1 (rs9923231) with stable warfarin dosage. Notably, CYP2C9 variant genotypes were significantly linked to an increased risk of hemorrhagic complications ( P  < 0.00001), VKORC1 did not demonstrate a similar association. CONCLUSION: The associations found between specific genetic variants and both stable warfarin dosage and bleeding risk might be the potential significance of gene detection in optimizing warfarin therapy for improving patient efficacy and safety.


Asunto(s)
Anticoagulantes , Pueblo Asiatico , Citocromo P-450 CYP2C9 , Polimorfismo de Nucleótido Simple , Vitamina K Epóxido Reductasas , Warfarina , Humanos , Citocromo P-450 CYP2C9/genética , Vitamina K Epóxido Reductasas/genética , Warfarina/efectos adversos , Warfarina/administración & dosificación , Femenino , Masculino , Persona de Mediana Edad , Anticoagulantes/efectos adversos , Anticoagulantes/administración & dosificación , Anciano , Pueblo Asiatico/genética , Hemorragia/inducido químicamente , Hemorragia/genética , China , Adulto , Genotipo , Estudios de Asociación Genética , Pueblos del Este de Asia
2.
Mov Disord ; 39(3): 498-509, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38148610

RESUMEN

BACKGROUND: Kinase D-interacting substrate of 220 kDa (KIDINS220) is a multifunctional scaffolding protein essential for neuronal development. It has been implicated in neurological diseases with either autosomal dominant (AD) or autosomal recessive (AR) inheritance patterns. The molecular mechanisms underlying the AR/AD dual nature of KIDINS220 remain elusive, posing challenges to genetic interpretation and clinical interventions. Moreover, increased KIDINS220 exhibited neurotoxicity, but its role in neurodevelopment remains unclear. OBJECTIVE: The aim was to investigate the genotype-phenotype correlations of KIDINS220 and elucidate its pathophysiological role in neuronal development. METHODS: Whole-exome sequencing was performed in a four-generation family with cerebral palsy. CRISPR/Cas9 was used to generate KIDINS220 mutant cell lines. In utero electroporation was employed to investigate the effect of KIDINS220 variants on neurogenesis in vivo. RESULTS: We identified in KIDINS220 a pathogenic nonsense variant (c.4177C > T, p.Q1393*) that associated with AD cerebral palsy. We demonstrated that the nonsense variants located in the terminal exon of KIDINS220 are gain-of-function (GoF) variants, which enable the mRNA to escape nonsense-mediated decay and produce a truncated yet functional KIDINS220 protein. The truncated protein exhibited significant resistance to calpain and consequently accumulated within cells, resulting in the hyperactivation of Rac1 and defects in neuronal development. CONCLUSIONS: Our findings demonstrate that the location of variants within KIDINS220 plays a crucial role in determining inheritance patterns and corresponding clinical outcomes. The proposed interaction between Rac1 and KIDINS220 provides new insights into the pathogenesis of cerebral palsy, implying potential therapeutic perspectives. © 2023 International Parkinson and Movement Disorder Society.


Asunto(s)
Parálisis Cerebral , Neuronas , Humanos , Neuronas/metabolismo , Transducción de Señal , Parálisis Cerebral/genética , Mutación con Ganancia de Función , Neurogénesis/genética , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Proteínas del Tejido Nervioso/genética
3.
J Cell Physiol ; 237(6): 2713-2723, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35621037

RESUMEN

TMEM67 (mecklin or MKS3) locates in the transition zone of cilia. Dysfunction of TMEM67 disrupts cilia-related signaling and leads to developmental defects of multiple organs in humans. Typical autosomal recessive TMEM67 defects cause partial overlapping phenotypes, including abnormalities in the brain, eyes, liver, kidneys, bones, and so forth. However, emerging reports of isolated nephronophthisis suggest the possibility of a broader phenotype spectrum. In this study, we analyzed the genetic data of cholestasis patients with no obvious extrahepatic involvement but with an unexplained high level of gamma-glutamyl transpeptidase (GGT). We identified five Han Chinese patients from three unrelated families with biallelic nonnull low-frequency TMEM67 variants. All variants were predicted pathogenic in silico, of which p. Arg820Ile and p. Leu144del were previously unreported. In vitro studies revealed that the protein levels of the TMEM67 variants were significantly decreased; however, their interaction with MKS1 remained unaffected. All the patients, aged 7-39 years old, had silently progressive cholestasis with elevated GGT but had normal bilirubin levels. Histological studies of liver biopsy of patients 1, 3, and 5 showed the presence of congenital hepatic fibrosis. We conclude that variants in TMEM67 are associated with a mild phenotype of unexplained, persistent, anicteric, and high GGT cholestasis without typical symptoms of TMEM67 defects; this possibility should be considered by physicians in gastroenterology and hepatology.


Asunto(s)
Colestasis , gamma-Glutamiltransferasa , Colestasis/genética , Enfermedades Genéticas Congénitas , Humanos , Cirrosis Hepática/genética , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Fenotipo , gamma-Glutamiltransferasa/genética
4.
Liver Int ; 42(2): 402-411, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34811877

RESUMEN

BACKGROUND & AIMS: Biallelic pathogenic variants in MYO5B cause microvillus inclusion disease (MVID), or familial intrahepatic cholestasis (FIC). The reported FIC patients are scarce and so the genotype-phenotype correlation has not been fully characterised. This study aimed to report more MYO5B-associated FIC patients and correlate genotypes to phenotypes in more detail. METHODS: The phenotype and genetic data of 12 newly diagnosed MYO5B-associated (including 11 FIC) patients, as well as 118 previously reported patients with available genotypes, were summarised. Only patients with biallelic MYO5B variants were enrolled. Nonsense, frameshift, canonical splice sites, initiation codon loss, and single exon or multiexon deletion were defined as null MYO5B variants. RESULTS: Phenotypically, 50 were isolated MVID, 47 involved both liver and intestine (combined), and 33 were isolated FIC (9 persistent, 15 recurrent, 3 transient, and 6 un-sub-classified) patients. The severity of intestinal manifestation was positively correlated to an increased number of null variants (ρ = 0.299, P = .001). All FIC patients carried at least one non-null variant, and the severity of cholestasis was correlated to the presence of a null variant (ρ = 0.420, P = .029). The proportion of FIC patients (16/29, 55%) harbouring missense/in-frame variants affecting the non-motor regions of MYO5B was significantly higher than that of MVID (3/25, 12%, P = .001) and combined patients (3/31, 10%, P = .000). 10 of the 29 FIC patients harboured missense/in-frame variants at the IQ motifs comparing to none in the 56 MVID and combined patients (P = .000). CONCLUSIONS: The phenotype of MYO5B deficiency was associated with MYO5B genotypes, the nullity or the domain affected.


Asunto(s)
Colestasis Intrahepática/genética , Mucolipidosis , Cadenas Pesadas de Miosina , Miosina Tipo V , Estudios de Asociación Genética , Humanos , Hígado/patología , Mucolipidosis/genética , Mucolipidosis/patología , Mutación , Cadenas Pesadas de Miosina/genética , Miosina Tipo V/genética
5.
J Med Genet ; 58(8): 514-525, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-32737136

RESUMEN

BACKGROUND: For many children with intrahepatic cholestasis and high-serum gamma-glutamyl transferase (GGT) activity, a genetic aetiology of hepatobiliary disease remains undefined. We sought to identify novel genes mutated in children with idiopathic high-GGT intrahepatic cholestasis, with clinical, histopathological and functional correlations. METHODS: We assembled a cohort of 25 children with undiagnosed high-GGT cholestasis and without clinical features of biliary-tract infection or radiological features of choledochal malformation, sclerosing cholangitis or cholelithiasis. Mutations were identified through whole-exome sequencing and targeted Sanger sequencing. We reviewed histopathological findings and assessed phenotypical effects of ZFYVE19 deficiency in cultured cells by immunofluorescence microscopy. RESULTS: Nine Han Chinese children harboured biallelic, predictedly complete loss-of-function pathogenic mutations in ZFYVE19 (c.314C>G, p.S105X; c.379C>T, p.Q127X; c.514C>T, p.R172X; c.547C>T, p.R183X; c.226A>G, p.M76V). All had portal hypertension and, at liver biopsy, histopathological features of the ductal plate malformation (DPM)/congenital hepatic fibrosis (CHF). Four children required liver transplantation for recurrent gastrointestinal haemorrhage. DPM/CHF was confirmed at hepatectomy, with sclerosing small-duct cholangitis. Immunostaining for two primary-cilium axonemal proteins found expression that was deficient intraluminally and ectopic within cholangiocyte cytoplasm. ZFYVE19 depletion in cultured cells yielded abnormalities of centriole and axoneme. CONCLUSION: Biallelic ZFYVE19 mutations can lead to high-GGT cholestasis and DPM/CHF in vivo. In vitro, they can lead to centriolar and axonemal abnormalities. These observations indicate that mutation in ZFYVE19 results, through as yet undefined mechanisms, in a ciliopathy.


Asunto(s)
Colangitis Esclerosante/genética , Colestasis Intrahepática/genética , Mutación/genética , Proteínas Oncogénicas/genética , Alelos , Secuencia de Aminoácidos , Línea Celular Tumoral , Enfermedades Genéticas Congénitas , Células HeLa , Humanos , Cirrosis Hepática , Secuenciación del Exoma/métodos
6.
Am J Hum Genet ; 103(5): 666-678, 2018 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-30343943

RESUMEN

Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the α1-subunit of the voltage-gated CaV2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed CaV2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.


Asunto(s)
Canales de Calcio Tipo R/genética , Proteínas de Transporte de Catión/genética , Contractura/genética , Discinesias/genética , Epilepsia/genética , Variación Genética/genética , Megalencefalia/genética , Espasmos Infantiles/genética , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Trastornos del Neurodesarrollo/genética
7.
J Cardiovasc Pharmacol ; 78(1): e105-e111, 2021 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-33958549

RESUMEN

ABSTRACT: Warfarin is a commonly prescribed anticoagulant for valvular heart disease that plays an important role in clinical management to prevent thrombotic events. In this study, we aim to perform a comprehensive study to investigate the genetic biomarkers of stable warfarin dose in the Han Chinese population. We performed an integrative study on 211 Han Chinese patients with valvular heart disease. A total of 40 single nucleotide polymorphisms (SNPs) in 10 important genes (CYP2C9, VKORC1, ABCB1, CYP4F2, APOE, PROC, GGCX, EPHX1, CALU, and SETD1A) which are involved in the warfarin metabolic pathway and equilibrium of coagulation and anticoagulation were selected. We applied MassARRAY technology to genotype the 40 SNPs identified in these Han Chinese patients. Our results showed that 13 SNPs on 6 genes (CYP2C9, VKORC1, ABCB1, PROC, EPHX1, and SETD1A) were associated with the individual stable warfarin dose. Two VKORC1 SNPs (rs9934438 and rs2359612) were the strongest genetic factors determining warfarin dose requirements (P = 8 × 10-6 and 9 × 10-6, respectively). Rs4889599 in SETD1A was first reported to be associated with warfarin dose at a significant level of 0.001 in our study (Padjust = 0.040 after Bonferroni correction). We discovered that genetic variants in CYP2C9, VKORC1, ABCB1, PROC, EPHX1, and SETD1A may affect the stable warfarin dose requirement in Han Chinese patients with valvular disease. The discovery of these potential genetic markers will facilitate the development of advanced personalized anticoagulation therapy in Han Chinese patients.


Asunto(s)
Anticoagulantes/administración & dosificación , Pueblo Asiatico/genética , Enfermedades de las Válvulas Cardíacas/cirugía , Implantación de Prótesis de Válvulas Cardíacas , Variantes Farmacogenómicas , Polimorfismo de Nucleótido Simple , Tromboembolia/prevención & control , Warfarina/administración & dosificación , Adulto , Anciano , Anticoagulantes/efectos adversos , Anticoagulantes/farmacocinética , China/epidemiología , Toma de Decisiones Clínicas , Femenino , Enfermedades de las Válvulas Cardíacas/diagnóstico , Enfermedades de las Válvulas Cardíacas/etnología , Implantación de Prótesis de Válvulas Cardíacas/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Farmacogenética , Pruebas de Farmacogenómica , Valor Predictivo de las Pruebas , Factores de Riesgo , Tromboembolia/diagnóstico , Tromboembolia/etnología , Factores de Tiempo , Resultado del Tratamiento , Warfarina/efectos adversos , Warfarina/farmacocinética
8.
Hum Mutat ; 41(2): 502-511, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31696999

RESUMEN

To assess the spectrum of pediatric clinical phenotypes in TJP2 disease, we reviewed records of our seven patients in whom intrahepatic cholestasis was associated with biallelic TJP2 variants (13; 12 novel) and correlated clinical manifestations with mutation type. The effect of a splicing variant was analyzed with a minigene assay. The effects of three missense variants were analyzed with protein expression in vitro. Our patients had both remitting and persistent cholestasis. Three exhibited growth retardation. Six responded to treatment with cholestyramine, ursodeoxycholic acid, or both. Two had cholecystolithiasis. None required liver transplantation or developed hepatocellular or cholangiocellular malignancy. None manifested extrahepatic disease not attributable to effects of cholestasis. The variant c.2180-5T>G resulted in exon 15 skipping with in-frame deletion of 32 amino acid residues in TJP2. The three missense variants decreased but did not abolish TJP2 expression. Patients with truncating or canonical splice-site variants had clinically more severe disease. TJP2 disease in children includes a full clinical spectrum of severity, with mild or intermittent forms as well as the severe and minimal forms hitherto described. Biallelic TJP2 variants must be considered in children with clinically intermittent or resolved intrahepatic cholestasis.


Asunto(s)
Colestasis Intrahepática/diagnóstico , Colestasis Intrahepática/genética , Predisposición Genética a la Enfermedad , Variación Genética , Proteína de la Zonula Occludens-2/genética , Edad de Inicio , Alelos , Sustitución de Aminoácidos , Biopsia , Biología Computacional/métodos , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Mutación , Linaje , Empalme del ARN , Secuenciación del Exoma
9.
Pharmacogenomics J ; 20(3): 408-414, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-31792370

RESUMEN

Tanshinone, a widely used Chinese patent medicine, has been confirmed to have various kinds of pharmacological effects although frequently causing cutaneous adverse drug reactions (cADRs). We aim to identify whether human leukocyte antigen (HLA) class I alleles are associated with tanshinone-induced cADRs in Han Chinese. The association study including 18 patients with tanshinone-induced cADRs, 67 tanshinone-tolerant volunteers, and two general population databases consisted of 10,689 and 169,995 healthy subjects was performed. The frequency of tanshinone-induced cADRs patients carrying HLA-A*02:01 was significantly higher when compared with the general control groups (OR = 6.25, Pc = 7.20 × 10-5; OR = 7.14, Pc = 8.00 × 10-6), and with the tolerant group (OR = 5.09, Pc = 0.024). The molecular docking assay confirmed high affinity of the ingredients of tanshinone towards HLA-A*02:01 (≤-7.5 kcal/mol). The result suggested HLA-A*02:01 may work as a promisingly predictive marker for tanshinone personalized therapy in Han Chinese.


Asunto(s)
Abietanos/efectos adversos , Alelos , Pueblo Asiatico/genética , Erupciones por Medicamentos/genética , Estudios de Asociación Genética/métodos , Antígeno HLA-A2/genética , Adolescente , Adulto , Anciano , Antiinfecciosos/efectos adversos , Erupciones por Medicamentos/diagnóstico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Simulación del Acoplamiento Molecular/métodos , Vigilancia de la Población/métodos , Adulto Joven
10.
J Cell Physiol ; 234(9): 16526-16539, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-30873621

RESUMEN

This study aims to investigate the role of microRNA-145 (miR-145) in protection against myocardial ischemia/reperfusion (I/R) injury in mice by regulating expression of granzyme K (GZMK) with the treatment of sevoflurane. The mice model of myocardial I/R injury was established by left coronary artery ligation. The expression of miR-145 and GZMK in myocardial tissues of mice was detected by Reverse transcription quantitative polymerase chain reaction and western blot analysis. The changes of the cardiac function and hemodynamics, pathological changes of myocardial tissues, the ultrastructure of cardiomyocytes, myocardial infarction area, and cardiomyocyte apoptosis were observed. The expression of the apoptosis-related protein cleaved-caspase-3, Bax, and Bcl-2 was detected by western blot analysis. The levels of malondialdehyde, myeloperoxidase, superoxide dismutase in myocardial tissues were detected by spectrophotometric colorimetry. The levels of interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor-α in the serum of mice were detected by the enzyme-linked immunosorbent assay. The level of oxidative stress and the expression of inflammatory factors increased in mice with myocardial I/R injury. Sevoflurane postconditioning could reduce myocardial I/R injury in mice. Sevoflurane postconditioning may protect myocardial I/R injury through miR-145-regulation of GZMK in mice. Inhibition of miR-145 expression could reduce the protective effect of sevoflurane posttreatment on myocardial I/R injury in mice. Low expression of GZMK could attenuate the inhibitory effect of miR-145 on myocardial I/R injury after sevoflurane treatment in mice. Our study suggests that sevoflurane postconditioning may protect against myocardial I/R injury by upregulating miR-145 expression and downregulating GZMK expression.

11.
N Engl J Med ; 374(3): 223-32, 2016 Jan 21.
Artículo en Inglés | MEDLINE | ID: mdl-26789871

RESUMEN

Background Human reproduction depends on the fusion of a mature oocyte with a sperm cell to form a fertilized egg. The genetic events that lead to the arrest of human oocyte maturation are unknown. Methods We sequenced the exomes of five members of a four-generation family, three of whom had infertility due to oocyte meiosis I arrest. We performed Sanger sequencing of a candidate gene, TUBB8, in DNA samples from these members, additional family members, and members of 23 other affected families. The expression of TUBB8 and all other ß-tubulin isotypes was assessed in human oocytes, early embryos, sperm cells, and several somatic tissues by means of a quantitative reverse-transcriptase-polymerase-chain-reaction assay. We evaluated the effect of the TUBB8 mutations on the assembly of the heterodimer consisting of one α-tubulin polypeptide and one ß-tubulin polypeptide (α/ß-tubulin heterodimer) in vitro, on microtubule architecture in HeLa cells, on microtubule dynamics in yeast cells, and on spindle assembly in mouse and human oocytes. Results We identified seven mutations in the primate-specific gene TUBB8 that were responsible for oocyte meiosis I arrest in 7 of the 24 families. TUBB8 expression is unique to oocytes and the early embryo, in which this gene accounts for almost all the expressed ß-tubulin. The mutations affect chaperone-dependent folding and assembly of the α/ß-tubulin heterodimer, disrupt microtubule behavior on expression in cultured cells, alter microtubule dynamics in vivo, and cause catastrophic spindle-assembly defects and maturation arrest on expression in mouse and human oocytes. Conclusions TUBB8 mutations have dominant-negative effects that disrupt microtubule behavior and oocyte meiotic spindle assembly and maturation, causing female infertility. (Funded by the National Basic Research Program of China and others.).


Asunto(s)
Infertilidad Femenina/genética , Meiosis/genética , Microtúbulos/patología , Mutación , Oocitos/fisiología , Huso Acromático/fisiología , Tubulina (Proteína)/genética , Adulto , Animales , Femenino , Humanos , Meiosis/fisiología , Ratones , Microtúbulos/fisiología , ARN
12.
Biol Proced Online ; 21: 20, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31636514

RESUMEN

BACKGROUND: Mammalian gonadal development is crucial for fertility. Sexual differentiation, meiosis and gametogenesis are critical events in the process of gonadal development. Abnormalities in any of these events may cause infertility. However, owing to the complexity of these developmental events, the underlying molecular mechanisms are not fully understood and require further research. RESULTS: In this study, we employed RNA sequencing to examine transcriptome profiles of murine female and male gonads at crucial stages of these developmental events. By bioinformatics analysis, we identified a group of candidate genes that may participate in sexual differentiation, including Erbb3, Erbb4, and Prkg2. One hundred and two and 134 candidate genes that may be important for female and male gonadal development, respectively, were screened by analyzing the global gene expression patterns of developing female and male gonads. Weighted gene co-expression network analysis was performed on developing female gonads, and we identified a gene co-expression module related to meiosis. By alternative splicing analysis, we found that cassette-type exon and alternative start sites were the main forms of alternative splicing in developing gonads. A considerable portion of differentially expressed and alternatively spliced genes were involved in meiosis. CONCLUSION: Taken together, our findings have enriched the gonadal transcriptome database and provided novel candidate genes and avenues to research the molecular mechanisms of sexual differentiation, meiosis, and gametogenesis. SUPPLEMENTARY INFORMATION: Supplementary information accompanies this paper at 10.1186/s12575-019-0108-y.

13.
Pharmacogenomics J ; 19(3): 277-285, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30237582

RESUMEN

Xuesaitong (XST) is mainly used to treat cardiovascular and cerebrovascular diseases, sometimes causing cutaneous adverse drug reactions (cADRs) with unknown mechanisms of pathogenicity or risk factors. We aimed to verify whether human leukocyte antigen (HLA) alleles are associated with XST-related cADRs in Han Chinese population. We carried out an association study including 12 subjects with XST-induced cADRs, 283 controls, and 28 XST-tolerant subjects. Five out of 12 patients with XST-induced cADRs carried HLA-C*12:02, and all of them received XST via intravenous drip. The carrier frequency of HLA-C*12:02 was significantly high compare to that of the control population (Pc = 4.4 × 10-4, odds ratio (OR) = 21.75, 95% CI = 5.78-81.88). Compared with that of the XST-tolerant group, the patients who received XST through intravenous drip presented a higher OR of cADRs (Pc = 0.011, OR = 27.00, 95% CI = 2.58-282.98). The results suggest that HLA-C*12:02 is a potentially predictive marker of XST-induced cADRs in Han Chinese, especially when XST is administered via intravenous drip.


Asunto(s)
Erupciones por Medicamentos/genética , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/genética , Medicamentos Herbarios Chinos/efectos adversos , Predisposición Genética a la Enfermedad/genética , Antígenos HLA-C/genética , Saponinas/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Pueblo Asiatico/genética , Femenino , Frecuencia de los Genes/genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven
14.
Bioinformatics ; 33(22): 3538-3548, 2017 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-29036410

RESUMEN

MOTIVATION: RNA editing generates post-transcriptional sequence alterations. Detection of RNA editing sites (RESs) typically requires the filtering of SNVs called from RNA-seq data using an SNP database, an obstacle that is difficult to overcome for most organisms. RESULTS: Here, we present a novel method named SPRINT that identifies RESs without the need to filter out SNPs. SPRINT also integrates the detection of hyper RESs from remapped reads, and has been fully automated to any RNA-seq data with reference genome sequence available. We have rigorously validated SPRINT's effectiveness in detecting RESs using RNA-seq data of samples in which genes encoding RNA editing enzymes are knock down or over-expressed, and have also demonstrated its superiority over current methods. We have applied SPRINT to investigate RNA editing across tissues and species, and also in the development of mouse embryonic central nervous system. A web resource (http://sprint.tianlab.cn) of RESs identified by SPRINT has been constructed. AVAILABILITY AND IMPLEMENTATION: The software and related data are available at http://sprint.tianlab.cn. CONTACT: weidong.tian@fudan.edu.cn. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Asunto(s)
Edición de ARN , ARN/química , Análisis de Secuencia de ARN/métodos , Programas Informáticos , Animales , Bases de Datos Genéticas , Genoma , Ratones , ARN/genética , Reproducibilidad de los Resultados
15.
BMC Med Genet ; 19(1): 139, 2018 08 07.
Artículo en Inglés | MEDLINE | ID: mdl-30086703

RESUMEN

BACKGROUND: Branchio-oto-renal (BOR) syndrome is a dominant autosomal disorder characterized by phenotypes such as hearing loss, branchial fistulae, preauricular pits, and renal abnormalities. EYA1, the human homolog of the Drosophila "eye absent" gene on chromosome 8q13.3, is recognized as one of the most important genes associated with BOR syndrome. METHODS: The proposita in this study was a 5-year-old Chinese girl with hearing loss, bilateral otitis media with effusion, microtia, facial hypoplasia, palatoschisis, and bilateral branchial cleft fistulae. The girl's family members, except two who were deceased, agreed to undergo clinical examination. We collected blood samples from 10 family members, including six who were affected by the syndrome. Genomic DNA was extracted and subjected to Sanger sequencing. A minigene assay was performed to confirm whether splicing signals were altered. In addition, we performed western blotting to determine alterations in protein levels of the wild-type and mutant gene. RESULTS: Clinical tests showed that some of the family members met the criteria for BOR syndrome. The affected members harbored a novel heterozygous nonsense variation in exon 11 of EYA1, whereas no unaffected member carried the mutation at this position. Functional experiments did not detect abnormal splicing at the RNA level; however, western blotting showed that the mutated protein was truncated. CONCLUSIONS: This study reports a novel mutation associated with BOR syndrome in a Chinese family. We highlight the usefulness of genetic testing in the diagnosis of BOR syndrome. Thus, we believe that this report would benefit clinicians in this field.


Asunto(s)
Síndrome Branquio Oto Renal/genética , Codón sin Sentido/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas Nucleares/genética , Proteínas Tirosina Fosfatasas/genética , Pueblo Asiatico , Preescolar , ADN/genética , Exones/genética , Femenino , Pérdida Auditiva/genética , Humanos , Masculino , Otitis Media/genética , Linaje , Fenotipo
16.
Hepatology ; 65(5): 1655-1669, 2017 05.
Artículo en Inglés | MEDLINE | ID: mdl-28027573

RESUMEN

Hereditary cholestasis in childhood and infancy with normal serum gamma-glutamyltransferase (GGT) activity is linked to several genes. Many patients, however, remain genetically undiagnosed. Defects in myosin VB (MYO5B; encoded by MYO5B) cause microvillus inclusion disease (MVID; MIM251850) with recurrent watery diarrhea. Cholestasis, reported as an atypical presentation in MVID, has been considered a side effect of parenteral alimentation. Here, however, we report on 10 patients who experienced cholestasis associated with biallelic, or suspected biallelic, mutations in MYO5B and who had neither recurrent diarrhea nor received parenteral alimentation. Seven of them are from two study cohorts, together comprising 31 undiagnosed low-GGT cholestasis patients; 3 are sporadic. Cholestasis in 2 patients was progressive, in 3 recurrent, in 2 transient, and in 3 uncategorized because of insufficient follow-up. Liver biopsy specimens revealed giant-cell change of hepatocytes and intralobular cholestasis with abnormal distribution of bile salt export pump (BSEP) at canaliculi, as well as coarse granular dislocation of MYO5B. Mass spectrometry of plasma demonstrated increased total bile acids, primary bile acids, and conjugated bile acids, with decreased free bile acids, similar to changes in BSEP-deficient patients. Literature review revealed that patients with biallelic mutations predicted to eliminate MYO5B expression were more frequent in typical MVID than in isolated-cholestasis patients (11 of 38 vs. 0 of 13). CONCLUSION: MYO5B deficiency may underlie 20% of previously undiagnosed low-GGT cholestasis. MYO5B deficiency appears to impair targeting of BSEP to the canalicular membrane with hampered bile acid excretion, resulting in a spectrum of cholestasis without diarrhea. (Hepatology 2017;65:1655-1669).


Asunto(s)
Subfamilia B de Transportador de Casetes de Unión a ATP/deficiencia , Colestasis Intrahepática/genética , Cadenas Pesadas de Miosina/genética , Miosina Tipo V/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/sangre , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Miembro 11 de la Subfamilia B de Transportador de Casetes de Unión al ATP , Transportadoras de Casetes de Unión a ATP/metabolismo , Ácidos y Sales Biliares/sangre , Colestasis Intrahepática/sangre , Colestasis Intrahepática/patología , Análisis Mutacional de ADN , Exoma , Femenino , Humanos , Lactante , Recién Nacido , Hígado/metabolismo , Hígado/patología , Masculino , Cadenas Pesadas de Miosina/metabolismo , Miosina Tipo V/metabolismo , Estudios Retrospectivos
17.
Mol Reprod Dev ; 85(1): 17-25, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-29266528

RESUMEN

Endometriosis is a benign disease, with malignant properties. A necessary step in the progression of endometriosis is tissue remodeling, which is coordinated by the activities of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs). This study evaluated the regulation of abnormal MMP and TIMP gene expression during endometriosis. Among the two genes families, promoter regions of MMP2, MMP3, MMP7, TIMP3, and TIMP4 were significantly altered in proliferative-phase endometriotic lesions compared to menstrual cycle-matched eutopic tissue from endometriosis-free women. In addition, a negative correlation was found between the DNA methylation status of the promoter region and transcript abundance of MMP2. Our findings suggest that changes in DNA methylation at the promoter region of MMP2 could underlie the changes in its expression in the ectopic endometria from patients with endometriosis.


Asunto(s)
Metilación de ADN/genética , Endometriosis/genética , Metaloproteinasa 2 de la Matriz/genética , Regiones Promotoras Genéticas/genética , Endometriosis/patología , Femenino , Regulación de la Expresión Génica/genética , Humanos , Metaloproteinasa 3 de la Matriz/genética , Metaloproteinasa 7 de la Matriz/genética , Ciclo Menstrual/fisiología , Inhibidor Tisular de Metaloproteinasa-3/genética , Inhibidores Tisulares de Metaloproteinasas/genética , Inhibidor Tisular de Metaloproteinasa-4
18.
Acta Derm Venereol ; 98(4): 401-405, 2018 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-29242946

RESUMEN

DRESS is one of the most severe drug reactions. The aim of this retrospective study was to summarize the clinical presentation, genetic predisposition and prognostic factors of DRESS. A total of 52 patients with DRESS, who were inpatients at a medical referral centre in Shanghai, China, from January 2011 to December 2016, were analysed retrospectively. All the patients had skin eruption, 83% had liver involvement, and ≤10% had other organ involvement. Mean cost of hospitalization was US$5,511±3,050. The 3 most common causative agents were allopurinol (18/52; 35%), salazosulphapyridine (11/52; 21%) and carbamazepine (5/52; 10%). HLA-B*5801 and HLA-B*1302 were associated with allopurinol-induced DRESS. HLA-B*1301 was related to salazosulphapyridine-induced DRESS. The mortality rate was 6% (3/52). Epstein-Barr virus DNA was found in 10 patients (19%) and indicated a poor prognosis. Human herpes virus 6 DNA was detected in 17 patients (33%) and was associated with autoimmune sequelae. Due to its high medical cost and sometimes poor prognosis, prevention of DRESS should be a high priority.


Asunto(s)
Alopurinol/efectos adversos , Carbamazepina/efectos adversos , ADN Viral/genética , Síndrome de Hipersensibilidad a Medicamentos/genética , Síndrome de Hipersensibilidad a Medicamentos/virología , Antígenos HLA-B/genética , Herpesvirus Humano 4/genética , Herpesvirus Humano 6/genética , Sulfasalazina/efectos adversos , Corticoesteroides/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , China , Síndrome de Hipersensibilidad a Medicamentos/tratamiento farmacológico , Síndrome de Hipersensibilidad a Medicamentos/mortalidad , Femenino , Predisposición Genética a la Enfermedad , Cadenas HLA-DRB1/genética , Herpesvirus Humano 4/patogenicidad , Herpesvirus Humano 6/patogenicidad , Costos de Hospital , Humanos , Inmunoglobulinas Intravenosas/administración & dosificación , Tiempo de Internación/economía , Masculino , Persona de Mediana Edad , Admisión del Paciente/economía , Fenotipo , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo , Activación Viral , Adulto Joven
19.
J Cell Mol Med ; 21(4): 802-815, 2017 04.
Artículo en Inglés | MEDLINE | ID: mdl-27885802

RESUMEN

p53-Transcriptional-regulated proteins interact with a large number of other signal transduction pathways in the cell, and a number of positive and negative autoregulatory feedback loops act upon the p53 response. P53 directly controls the POMC/α-MSH productions induced by ultraviolet (UV) and is associated with UV-independent pathological pigmentation. When identifying the causative gene of dyschromatosis universalis hereditaria (DUH), we found three mutations encoding amino acid substitutions in the gene SAM and SH3 domain containing 1 (SASH1), and SASH1 was associated with guanine nucleotide-binding protein subunit-alpha isoforms short (Gαs). However, the pathological gene and pathological mechanism of DUH remain unknown for about 90 years. We demonstrate that SASH1 is physiologically induced by p53 upon UV stimulation and SASH and p53 is reciprocally induced at physiological and pathophysiological conditions. SASH1 is regulated by a novel p53/POMC/α-MSH/Gαs/SASH1 cascade to mediate melanogenesis. A novel p53/POMC/Gαs/SASH1 autoregulatory positive feedback loop is regulated by SASH1 mutations to induce pathological hyperpigmentation phenotype. Our study demonstrates that a novel p53/POMC/Gαs/SASH1 autoregulatory positive feedback loop is regulated by SASH1 mutations to induce pathological hyperpigmentation phenotype.


Asunto(s)
Cromograninas/metabolismo , Retroalimentación Fisiológica , Subunidades alfa de la Proteína de Unión al GTP Gs/metabolismo , Hiperpigmentación/genética , Hiperpigmentación/patología , Mutación/genética , Proopiomelanocortina/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Supresoras de Tumor/genética , Adolescente , Secuencia de Bases , Línea Celular , Humanos , Masculino , Melaninas/metabolismo , Melanosomas/metabolismo , Trastornos de la Pigmentación/congénito , Trastornos de la Pigmentación/genética , Trastornos de la Pigmentación/patología , Unión Proteica/efectos de la radiación , Transducción de Señal/efectos de la radiación , Enfermedades Cutáneas Genéticas/genética , Enfermedades Cutáneas Genéticas/patología , Rayos Ultravioleta , Regulación hacia Arriba/efectos de la radiación
20.
J Cell Mol Med ; 21(10): 2465-2480, 2017 10.
Artículo en Inglés | MEDLINE | ID: mdl-28382689

RESUMEN

We previously reported that three point mutations in SASH1 and mutated SASH1 promote melanocyte migration in dyschromatosis universalis hereditaria (DUH) and a novel p53/POMC/Gαs/SASH1 autoregulatory positive feedback loop is regulated by SASH1 mutations to induce pathological hyperpigmentation phenotype. However, the underlying mechanism of molecular regulation to cause this hyperpigmentation disorder still remains unclear. In this study, we aimed to investigate the molecular mechanism undergirding hyperpigmentation in the dyschromatosis disorder. Our results revealed that SASH1 binds with MAP2K2 and is induced by p53-POMC-MC1R signal cascade to enhance the phosphorylation level of ERK1/2 and CREB. Moreover, increase in phosphorylated ERK1/2 and CREB levels and melanogenesis-specific molecules is induced by mutated SASH1 alleles. Together, our results suggest that a novel SASH1/MAP2K2 crosstalk connects ERK1/2/CREB cascade with p53-POMC-MC1R cascade to cause hyperpigmentation phenotype of DUH.


Asunto(s)
Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Hiperpigmentación/metabolismo , MAP Quinasa Quinasa 2/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Línea Celular Tumoral , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Quinasas MAP Reguladas por Señal Extracelular/genética , Células HEK293 , Humanos , Hiperpigmentación/genética , MAP Quinasa Quinasa 2/genética , Modelos Biológicos , Mutación , Trastornos de la Pigmentación/congénito , Trastornos de la Pigmentación/genética , Trastornos de la Pigmentación/metabolismo , Unión Proteica , Interferencia de ARN , Transducción de Señal/genética , Enfermedades Cutáneas Genéticas/genética , Enfermedades Cutáneas Genéticas/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteínas Supresoras de Tumor/genética
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